Mathematical Model of HPV Provides Insight into Impacts of Risk Factors and Vaccine

Kim discusses a study by Barnabas and colleagues in PLoS Medicine in which the researchers used a mathematical model to assess the effect of sexual transmission of HPV 16 in a Finnish population

Costs and Cost-Effectiveness of 9-Valent Human Papillomavirus (HPV) Vaccination in Two East African Countries

Background: Current prophylactic vaccines against human papillomavirus (HPV) target two of the most oncogenic types, HPV-16 and -18, which contribute to roughly 70% of cervical cancers worldwide. Second-generation HPV vaccines include a 9-valent vaccine, which targets five additional oncogenic HPV types (i.e., 31, 33, 45, 52, and 58) that contribute to another 15–30% of cervical cancer cases. The objective of this study was to determine a range of vaccine costs for which the 9-valent vaccine would be cost-effective in comparison to the current vaccines in two less developed countries (i.e., Kenya and Uganda). Methods and Findings: The analysis was performed using a natural history disease simulation model of HPV and cervical cancer. The mathematical model simulates individual women from an early age and tracks health events and resource use as they transition through clinically-relevant health states over their lifetime. Epidemiological data on HPV prevalence and cancer incidence were used to adapt the model to Kenya and Uganda. Health benefit, or effectiveness, from HPV vaccination was measured in terms of life expectancy, and costs were measured in international dollars (I$). The incremental cost of the 9-valent vaccine included the added cost of the vaccine counterbalanced by costs averted from additional cancer cases prevented. All future costs and health benefits were discounted at an annual rate of 3$9.7 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$5.2 and I$16.2 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP where the 9-valent vaccine would be considered cost-effective, the thresholds of added costs associated with the 9-valent vaccine were I$27.3, I$14.5 and I$45.3 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. In Uganda, vaccination with the 9-valent vaccine was very cost-effective when the added cost of the 9-valent vaccine did not exceed I$8.3 per vaccinated girl. To be considered very cost-effective, the added cost per vaccinated girl could go up to I$4.5 and I$13.7 in the worst-case and best-case scenarios, respectively. At a willingness-to-pay threshold of three times per-capita GDP, the thresholds of added costs associated with the 9-valent vaccine were I$23.4, I$12.6 and I$38.4 per vaccinated girl for the base case, worst-case and best-case scenarios, respectively. Conclusions: This study provides a threshold range of incremental costs associated with the 9-valent HPV vaccine that would make it a cost-effective intervention in comparison to currently available HPV vaccines in Kenya and Uganda. These prices represent a 71$5 per dose) for the currently available 2- and 4-valent vaccines in Kenya and Uganda, respectively. Despite evidence of cost-effectiveness, critical challenges around affordability and feasibility of HPV vaccination and other competing needs in low-resource settings such as Kenya and Uganda remain

TLR4 and Insulin Resistance

Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4), involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) and endogenous ligands (e.g., free fatty acids) which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS) on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity

Imaging for the Diagnosis and Management of Traumatic Brain Injury

To understand the role of imaging in traumatic brain injury (TBI), it is important to appreciate that TBI encompasses a heterogeneous group of intracranial injuries and includes both insults at the time of impact and a deleterious secondary cascade of insults that require optimal medical and surgical management. Initial imaging identifies the acute primary insult that is essential to diagnosing TBI, but serial imaging surveillance is also critical to identifying secondary injuries such as cerebral herniation and swelling that guide neurocritical management. Computed tomography (CT) is the mainstay of TBI imaging in the acute setting, but magnetic resonance tomography (MRI) has better diagnostic sensitivity for nonhemorrhagic contusions and shear-strain injuries. Both CT and MRI can be used to prognosticate clinical outcome, and there is particular interest in advanced applications of both techniques that may greatly improve the sensitivity of conventional CT and MRI for both the diagnosis and prognosis of TBI

Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States

Objective To assess the cost effectiveness of including preadolescent boys in a routine human papillomavirus (HPV) vaccination programme for preadolescent girls

The Chemical and Ionization Conditions in Weak Mg II Absorbers

We present an analysis of the chemical and ionization conditions in a sample of 100 weak Mg II absorbers identified in the VLT/UVES archive of quasar spectra. Using a host of low ionization lines associated with each absorber in this sample, and on the basis of ionization models, we infer that the metallicity in a significant fraction of weak Mg II clouds is constrained to values of solar or higher, if they are sub-Lyman limit systems. Based on the observed constraints, we present a physical picture in which weak Mg II absorbers are predominantly tracing two different astrophysical processes/structures. A significant population of weak Mg II clouds, those in which N(Fe II) is much less than N(Mg II), identified at both low (z ~ 1) and high (z ~ 2) redshift, are potentially tracing gas in the extended halos of galaxies, analogous to the Galactic high velocity clouds. These absorbers might correspond to alpha-enhanced interstellar gas expelled from star-forming galaxies, in correlated supernova events. On the other hand, N(FeII) approximately equal to N(Mg II) clouds, which are prevalent only at lower redshifts (z < 1.5), must be tracing Type Ia enriched gas in small, high metallicity pockets in dwarf galaxies, tidal debris, or other intergalactic structures.Comment: 35 pages (including tables & figures). Accepted for publication in ApJ. A high resolution version of the paper is available at "http://www.astro.wisc.edu/~anand/weakMgII.pdf

The Kinematic Evolution of Strong MgII Absorbers

We consider the evolution of strong (W_r(2796) > 0.3A) MgII absorbers, most of which are closely related to luminous galaxies. Using 20 high resolution quasar spectra from the VLT/UVES public archive, we examine 33 strong MgII absorbers in the redshift range 0.3 < z < 2.5. We compare and supplement this sample with 23 strong MgII absorbers at 0.4 < z < 1.4 observed previously with HIRES/Keck. We find that neither equivalent width nor kinematic spread (the optical depth weighted second moment of velocity) of MgII2796 evolve. However, the kinematic spread is sensitive to the highest velocity component, and therefore not as sensitive to additional weak components at intermediate velocities relative to the profile center. The fraction of absorbing pixels within the full velocity range of the system does show a trend of decreasing with decreasing redshift. Most high redshift systems (14/20) exhibit absorption over the entire system velocity range, which differs from the result for low redshift systems (18/36) at the 95% level. This leads to a smaller number of separate subsystems for high redshift systems because weak absorping components tend to connect the stronger regions of absorption. We hypothesize that low redshift MgII profiles are more likely to represent well formed galaxies, many of which have kinematics consistent with a disk/halo structure. High redshift MgII profiles are more likely to show evidence of complex protogalactic structures, with multiple accretion or outflow events. Although these results are derived from measurements of gas kinematics, they are consistent with hierarchical galaxy formation evidenced by deep galaxy surveys.Comment: Accepted to the Astrophysical Journa

Prevention of HPV-Related Cancers in Norway: Cost-Effectiveness of Expanding the HPV Vaccination Program to Include Pre-Adolescent Boys

Background: Increasingly, countries have introduced female vaccination against human papillomavirus (HPV), causally linked to several cancers and genital warts, but few have recommended vaccination of boys. Declining vaccine prices and strong evidence of vaccine impact on reducing HPV-related conditions in both women and men prompt countries to reevaluate whether HPV vaccination of boys is warranted. Methods: A previously-published dynamic model of HPV transmission was empirically calibrated to Norway. Reductions in the incidence of HPV, including both direct and indirect benefits, were applied to a natural history model of cervical cancer, and to incidence-based models for other non-cervical HPV-related diseases. We calculated the health outcomes and costs of the different HPV-related conditions under a gender-neutral vaccination program compared to a female-only program. Results: Vaccine price had a decisive impact on results. For example, assuming 71% coverage, high vaccine efficacy and a reasonable vaccine tender price of $75 per dose, we found vaccinating both girls and boys fell below a commonly cited cost-effectiveness threshold in Norway ($83,000/quality-adjusted life year (QALY) gained) when including vaccine benefit for all HPV-related diseases. However, at the current market price, including boys would not be considered ‘good value for money.’ For settings with a lower cost-effectiveness threshold ($30,000/QALY), it would not be considered cost-effective to expand the current program to include boys, unless the vaccine price was less than$36/dose. Increasing vaccination coverage to 90% among girls was more effective and less costly than the benefits achieved by vaccinating both genders with 71% coverage. Conclusions: At the anticipated tender price, expanding the HPV vaccination program to boys may be cost-effective and may warrant a change in the current female-only vaccination policy in Norway. However, increasing coverage in girls is uniformly more effective and cost-effective than expanding vaccination coverage to boys and should be considered a priority

Cost-effectiveness of cervical cancer screening with primary human papillomavirus testing in Norway

Background: New screening technologies and vaccination against human papillomavirus (HPV), the necessary cause of cervical cancer, may impact optimal approaches to prevent cervical cancer. We evaluated the cost-effectiveness of alternative screening strategies to inform cervical cancer prevention guidelines in Norway. Methods: We leveraged the primary epidemiologic and economic data from Norway to contextualise a simulation model of HPV-induced cervical cancer. The current cytology-only screening was compared with strategies involving cytology at younger ages and primary HPV-based screening at older ages (31/34+ years), an option being actively deliberated by the Norwegian government. We varied the switch-age, screening interval, and triage strategies for women with HPV-positive results. Uncertainty was evaluated in sensitivity analysis. Results: Current cytology-only screening was less effective and more costly than strategies that involve switching to primary HPV testing in older ages. For unvaccinated women, switching at age 34 years to primary HPV testing every 4 years was optimal given the Norwegian cost-effectiveness threshold ($83 000 per year of life saved). For vaccinated women, a 6-year screening interval was cost-effective. When we considered a wider range of strategies, we found that an earlier switch to HPV testing (at age 31 years) may be preferred. Conclusions: Strategies involving a switch to HPV testing for primary screening in older women is expected to be cost-effective compared with current recommendations in Norway

A survey of weak MgII absorbers at redshift <z>=1.78

The exact nature of weak MgII absorbers (those with W_r(2796) < 0.3 A) is a matter of debate, but most are likely related to areas of local star formation or supernovae activity outside of giant galaxies. Using 18 QSO spectra obtained with the Ultra-Violet Echelle Spectrograph (UVES) on the Very Large Telescope (VLT), we have conducted a survey for weak MgII absorbers at 1.4 < z < 2.4. We searched a redshift path length of 8.51, eliminating regions badly contaminated by atmospheric absorption so that the survey is close to 100% complete to W_r(2796) = 0.02 A. We found a total of 9 weak absorbers, yielding a number density of absorbers of dN/dz = 1.06 +/- 0.12 for 0.02 <= W_r(2796) < 0.3 A. Narayanan et al. (2005) found dN/dz = 1.00 +/- 0.20 at 0 < z < 0.3 and Churchill et al. (1999) found dN/dz = 1.74 +/- 0.10 at 0.4 < z < 1.4. Therefore, the population of weak MgII absorbers appears to peak at z~1. We explore the expected evolution of the absorber population subject to a changing extragalactic background radiation (EBR) from z = 0.9 to z = 1.78 (the median redshift of our survey), and find that the result is higher than the observed value. We point out that the peak epoch for weak MgII absorption at z~1 may coincide with the peak epoch of global star formation in the dwarf galaxy environment.Comment: 25 pages, 14 figures, to be published in ApJ 01 March 2006, v639,